The lung branches out from bronchi and is gradually subdivided finely to form the eventual baggy structures which are referred to as “alveoli (or alveolus)”. The alveolus is composed of alveolar epithelial cells, vascular cells, and extracellular matrices (such as elastin or collagen). The alveolus is an important site where gas exchange in the body is conducted.
Pulmonary emphysema is a symptom where the alveolar walls are destroyed and the microstructures of the alveoli are hollowed out. Pulmonary emphysema reduces gas exchange efficiency and the elastic recoil of the whole lung, and it eventually lowers pulmonary functions.
It was known that inflammatory cells, such as alveolar macrophages or neutrophiles recruited into the lung, were strongly implicated in pulmonary emphysema which were activated by smoking, air pollution, noxious gas or the like (Barnes, P. J. et al., Nature Reviews/Drug Discovery, Vol. 1, 437-446 (2002)). It was reported that the macrophages and neutrophiles were activated by harmful substances in tobacco smoke or polluted air (although the detailed mechanism is unknown) and released substances (such as cytokines or proteases) capable of enhancing inflammation to take part in the destruction of the alveolar walls (Barnes, P. J. et al., Pharmacol Rev. 2004 December; 56(4):515-48).
At present, bronchodilators which improve the restriction of airflow, such as anticholinergic agents and β2 receptor stimulants, are widely used as therapeutic agents for pulmonary emphysema. However, they have not been able to alleviate the destruction of pulmonary alveoli and to retard the progression of the pulmonary emphysema itself. The use of anti-inflammatory agents represented by steroids is recommended in the acute exacerbation stage of chronic obstructive pulmonary diseases (COPD), i.e., cases involving infection and deterioration of pulmonary functions. It has, however, been reported that they are ineffective against the pulmonary emphysema itself. As pertinent art, azithromycins having a 15-membered ring were reported to display effectiveness against non-infectious inflammatory diseases (Japanese Published Application 2004-531539; JPA2004531539 or WO2002/087596). However, it was also pointed out that 14-membered macrolides differ from 15-membered macrolides with respect to pharmacological actions including anti-inflammatory action (ibid.).